The ultimate goal of the Molecular Oncology Program Project (MOPP) is to develop more effective therapies for human cancer based on a better mechanistic understanding of tumor cell survival and drug resistance. The goal will be pursued through close integration of original laboratory studies on molecular mechanisms with innovative clinical trials. To achieve this goal, collaborations between basic scientists and clinical investigators are integral to each research project: MOPP comprises three component research project, three cores, and nine clinical protocols. All the research projects will use myeloma as a paradigm, or model, to study mechanisms of tumor cell survival and treatment response. Observations made in this model will also be extended to other cancers, including breast and ovarian cancer. Project I will investigate the hypothesis that the tumor microenvironment influences drug response by conferring cell adhesion-mediated drug resistance. Myeloma cell lines by adhesion improves treatment response to chemotherapy drugs and radiation. Project II malignant progression through regulation of apoptotic mechanisms that also induce resistance to chemotherapy. This hypothesis will be evaluated in myeloma studies and a phase II clinical trial of neoadjuvant chemotherapy in breast alterations of topoisomerases I and II are involved in drug resistance to inhibitors of these enzymes. Laboratory studies myeloma, AML, NHL, and CLL, as well as certain solid tumors. Research in the component projects will be supported by three cores, including the Administrative Core, the Pathology Core, and the Clinical Trials Core. The MOPP research projects will e significantly enhanced by the highly collaborative nature of these closely integrated laboratory and clinical studies of cancer therapeutics. Results of these studies will provide new insights into the molecular mechanisms of tumor cell killing and drug resistance that will be directly translated into more effective cancer therapies.